Publications by authors named "Nuno D Pires"

13 Publications

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Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice.

Nat Metab 2019 08 19;1(8):830-843. Epub 2019 Aug 19.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 °C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.
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http://dx.doi.org/10.1038/s42255-019-0101-4DOI Listing
August 2019

Genetic dissection of the miR-200-Zeb1 axis reveals its importance in tumor differentiation and invasion.

Nat Commun 2018 11 7;9(1):4671. Epub 2018 Nov 7.

Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern-Weg 7, 8093, Zürich, Switzerland.

The epithelial-to-mesenchymal transition (EMT) is an important mechanism for cancer progression and metastasis. Numerous in vitro and tumor-profiling studies point to the miR-200-Zeb1 axis as crucial in regulating this process, yet in vivo studies involving its regulation within a physiological context are lacking. Here, we show that miR-200 ablation in the Rip-Tag2 insulinoma mouse model induces beta-cell dedifferentiation, initiates an EMT expression program, and promotes tumor invasion. Strikingly, disrupting the miR-200 sites of the endogenous Zeb1 locus causes a similar phenotype. Reexpressing members of the miR-200 superfamily in vitro reveals that the miR-200c family and not the co-expressed and closely related miR-141 family is responsible for regulation of Zeb1 and EMT. Our results thus show that disrupting the in vivo regulation of Zeb1 by miR-200c is sufficient to drive EMT, thus highlighting the importance of this axis in tumor progression and invasion and its potential as a therapeutic target.
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http://dx.doi.org/10.1038/s41467-018-07130-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220299PMC
November 2018

BATLAS: Deconvoluting Brown Adipose Tissue.

Cell Rep 2018 10;25(3):784-797.e4

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland. Electronic address:

Recruitment and activation of thermogenic adipocytes have received increasing attention as a strategy to improve systemic metabolic control. The analysis of brown and brite adipocytes is complicated by the complexity of adipose tissue biopsies. Here, we provide an in-depth analysis of pure brown, brite, and white adipocyte transcriptomes. By combining mouse and human transcriptome data, we identify a gene signature that can classify brown and white adipocytes in mice and men. Using a machine-learning-based cell deconvolution approach, we develop an algorithm proficient in calculating the brown adipocyte content in complex human and mouse biopsies. Applying this algorithm, we can show in a human weight loss study that brown adipose tissue (BAT) content is associated with energy expenditure and the propensity to lose weight. This online available tool can be used for in-depth characterization of complex adipose tissue samples and may support the development of therapeutic strategies to increase energy expenditure in humans.
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http://dx.doi.org/10.1016/j.celrep.2018.09.044DOI Listing
October 2018

Identification of Parent-of-Origin-Dependent QTLs Using Bulk-Segregant Sequencing (Bulk-Seq).

Methods Mol Biol 2018 ;1675:361-371

Department of Plant and Microbial Biology, Zürich-Basel Plant Science Center, University of Zürich, Zollikerstrasse 107, 8008, Zürich, Switzerland.

Parent-of-origin effects play important roles in plant reproduction and are often mediated by epigenetic modifications at the histone or DNA level. However, the genetic basis underlying these modifications can be challenging to identify. Here, we describe an approach (Bulk-Seq) that can be used to map loci mediating parent-of-origin-dependent effects using whole-genome sequencing of pools of DNA.
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http://dx.doi.org/10.1007/978-1-4939-7318-7_21DOI Listing
June 2018

A subunit of the oligosaccharyltransferase complex is required for interspecific gametophyte recognition in Arabidopsis.

Nat Commun 2016 Mar 11;7:10826. Epub 2016 Mar 11.

Department of Plant and Microbial Biology and Zürich-Basel Plant Science Center, University of Zürich, Zollikerstrasse 107, 8008 Zürich, Switzerland.

Species-specific gamete recognition is a key premise to ensure reproductive success and the maintenance of species boundaries. During plant pollen tube (PT) reception, gametophyte interactions likely allow the species-specific recognition of signals from the PT (male gametophyte) by the embryo sac (female gametophyte), resulting in PT rupture, sperm release, and double fertilization. This process is impaired in interspecific crosses between Arabidopsis thaliana and related species, leading to PT overgrowth and a failure to deliver the sperm cells. Here we show that ARTUMES (ARU) specifically regulates the recognition of interspecific PTs in A. thaliana. ARU, identified in a genome-wide association study (GWAS), exclusively influences interspecific--but not intraspecific--gametophyte interactions. ARU encodes the OST3/6 subunit of the oligosaccharyltransferase complex conferring protein N-glycosylation. Our results suggest that glycosylation patterns of cell surface proteins may represent an important mechanism of gametophyte recognition and thus speciation.
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http://dx.doi.org/10.1038/ncomms10826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792959PMC
March 2016

Quantitative Genetics Identifies Cryptic Genetic Variation Involved in the Paternal Regulation of Seed Development.

PLoS Genet 2016 Jan 26;12(1):e1005806. Epub 2016 Jan 26.

Department of Plant and Microbial Biology and Zurich-Basel Plant Science Center, University of Zurich, Zürich, Switzerland.

Embryonic development requires a correct balancing of maternal and paternal genetic information. This balance is mediated by genomic imprinting, an epigenetic mechanism that leads to parent-of-origin-dependent gene expression. The parental conflict (or kinship) theory proposes that imprinting can evolve due to a conflict between maternal and paternal alleles over resource allocation during seed development. One assumption of this theory is that paternal alleles can regulate seed growth; however, paternal effects on seed size are often very low or non-existent. We demonstrate that there is a pool of cryptic genetic variation in the paternal control of Arabidopsis thaliana seed development. Such cryptic variation can be exposed in seeds that maternally inherit a medea mutation, suggesting that MEA acts as a maternal buffer of paternal effects. Genetic mapping using recombinant inbred lines, and a novel method for the mapping of parent-of-origin effects using whole-genome sequencing of segregant bulks, indicate that there are at least six loci with small, paternal effects on seed development. Together, our analyses reveal the existence of a pool of hidden genetic variation on the paternal control of seed development that is likely shaped by parental conflict.
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http://dx.doi.org/10.1371/journal.pgen.1005806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727937PMC
January 2016

Seed evolution: parental conflicts in a multi-generational household.

Authors:
Nuno D Pires

Biomol Concepts 2014 Mar;5(1):71-86

Seeds are multi-generational structures containing a small embryonic plant enclosed in layers of diverse parental origins. The evolution of seeds was a pinnacle in an evolutionary trend towards a progressive retention of embryos and gametes within parental tissue. This strategy, which dates back to the first land plants, allowed an increased protection and nourishing of the developing embryo. Flowering plants took parental control one step further with the evolution of a biparental endosperm that derives from a second parallel fertilization event. The endosperm directly nourishes the developing embryo and allows not only the maternal genes, but also paternal genes, to play an active role during seed development. The appearance of an endosperm set the conditions for the manifestation of conflicts of interest between maternal and paternal genomes over the allocation of resources to the developing embryos. As a consequence, a dynamic balance was established between maternal and paternal gene dosage in the endosperm, and maintaining a correct balance became essential to ensure a correct seed development. This balance was achieved in part by changes in the genetic constitution of the endosperm and through epigenetic mechanisms that allow a differential expression of alleles depending on their parental origin. This review discusses the evolutionary steps that resulted in the appearance of seeds and endosperm, and the epigenetic and genetic mechanisms that allow a harmonious coinhabitance of multiple generations within a single seed.
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http://dx.doi.org/10.1515/bmc-2013-0034DOI Listing
March 2014

Different yet similar: evolution of imprinting in flowering plants and mammals.

F1000Prime Rep 2014 1;6:63. Epub 2014 Aug 1.

Institute of Plant Biology & Zürich-Basel Plant Science Center, University of Zürich Zollikerstrasse 107, CH-8008 Zürich Switzerland.

Genomic imprinting refers to a form of epigenetic gene regulation whereby alleles are differentially expressed in a parent-of-origin-dependent manner. Imprinting evolved independently in flowering plants and in therian mammals in association with the elaboration of viviparity and a placental habit. Despite the striking differences in plant and animal reproduction, genomic imprinting shares multiple characteristics between them. In both groups, imprinted expression is controlled, at least in part, by DNA methylation and chromatin modifications in cis-regulatory regions, and many maternally and paternally expressed genes display complementary dosage-dependent effects during embryogenesis. This suggests that genomic imprinting evolved in response to similar selective pressures in flowering plants and mammals. Nevertheless, there are important differences between plant and animal imprinting. In particular, genomic imprinting has been shown to be more flexible and evolutionarily labile in plants. In mammals, imprinted genes are organized mainly in highly conserved clusters, whereas in plants they occur in isolation throughout the genome and are affected by local gene duplications. There is a large degree of intra- and inter-specific variation in imprinted gene expression in plants. These differences likely reflect the distinct life cycles and the different evolutionary dynamics that shape plant and animal genomes.
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http://dx.doi.org/10.12703/P6-63DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126536PMC
August 2014

Recruitment and remodeling of an ancient gene regulatory network during land plant evolution.

Proc Natl Acad Sci U S A 2013 Jun 20;110(23):9571-6. Epub 2013 May 20.

Department of Plant Sciences, University of Oxford, Oxford OX1 3RB, United Kingdom.

The evolution of multicellular organisms was made possible by the evolution of underlying gene regulatory networks. In animals, the core of gene regulatory networks consists of kernels, stable subnetworks of transcription factors that are highly conserved in distantly related species. However, in plants it is not clear when and how kernels evolved. We show here that RSL (ROOT HAIR DEFECTIVE SIX-LIKE) transcription factors form an ancient land plant kernel controlling caulonema differentiation in the moss Physcomitrella patens and root hair development in the flowering plant Arabidopsis thaliana. Phylogenetic analyses suggest that RSL proteins evolved in aquatic charophyte algae or in early land plants, and have been conserved throughout land plant radiation. Genetic and transcriptional analyses in loss of function A. thaliana and P. patens mutants suggest that the transcriptional interactions in the RSL kernel were remodeled and became more hierarchical during the evolution of vascular plants. We predict that other gene regulatory networks that control development in derived groups of plants may have originated in the earliest land plants or in their ancestors, the Charophycean algae.
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http://dx.doi.org/10.1073/pnas.1305457110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677440PMC
June 2013

How to fine-tune an epigenetic switch.

Dev Cell 2012 Sep;23(3):453-4

Institute of Plant Biology and Zürich-Basel Plant Science Center, University of Zürich, CH-8008 Zürich, Switzerland.

Arabidopsis does not flower in winter because FLC represses flowering genes, but prolonged cold exposure silences FLC, allowing flowering in spring. How do plants recalibrate this switch to adapt to different climates? Reporting in Science, Coustham et al. (2012) found that tweaking a Polycomb target sequence may do the trick.
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http://dx.doi.org/10.1016/j.devcel.2012.08.014DOI Listing
September 2012

Morphological evolution in land plants: new designs with old genes.

Philos Trans R Soc Lond B Biol Sci 2012 Feb;367(1588):508-18

Department of Plant Sciences, University of Oxford, South Parks Road, Oxford OX1 3RB, UK.

The colonization and radiation of multicellular plants on land that started over 470 Ma was one of the defining events in the history of this planet. For the first time, large amounts of primary productivity occurred on the continental surface, paving the way for the evolution of complex terrestrial ecosystems and altering global biogeochemical cycles; increased weathering of continental silicates and organic carbon burial resulted in a 90 per cent reduction in atmospheric carbon dioxide levels. The evolution of plants on land was itself characterized by a series of radical transformations of their body plans that included the formation of three-dimensional tissues, de novo evolution of a multicellular diploid sporophyte generation, evolution of multicellular meristems, and the development of specialized tissues and organ systems such as vasculature, roots, leaves, seeds and flowers. In this review, we discuss the evolution of the genes and developmental mechanisms that drove the explosion of plant morphologies on land. Recent studies indicate that many of the gene families which control development in extant plants were already present in the earliest land plants. This suggests that the evolution of novel morphologies was to a large degree driven by the reassembly and reuse of pre-existing genetic mechanisms.
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http://dx.doi.org/10.1098/rstb.2011.0252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248709PMC
February 2012

RSL genes are sufficient for rhizoid system development in early diverging land plants.

Development 2011 Jun;138(11):2273-81

Department of Plant Sciences, University of Oxford, South Parks Road, Oxford OX1 3RB, UK.

Land plants are anchored to their substratum from which essential inorganic nutrients are taken up. These functions are carried out by a system of rhizoids in early diverging groups of land plants, such as mosses, liverworts and hornworts. Physcomitrella patens RHD SIX-LIKE1 (PpRSL1) and PpRSL2 transcription factors are necessary for rhizoid development in mosses. Similar proteins, AtRHD6 and AtRSL1, control the development of root hairs in Arabidopsis thaliana. Auxin positively regulates root hair development independently of AtRHD6 and AtRSL1 in A. thaliana but the regulatory interactions between auxin and PpRSL1 and PpRSL2 are unknown. We show here that co-expression of PpRSL1 and PpRSL2 is sufficient for the development of the rhizoid system in the moss P. patens; constitutive expression of PpRSL1 and PpRSL2 converts developing leafy shoot axes (gametophores) into rhizoids. During wild-type development, PpRSL1 and PpRSL2 are expressed in the specialized cells that develop rhizoids, indicating that cell-specific expression of PpRSL1 and PpRSL2 is sufficient to promote rhizoid differentiation during wild-type P. patens development. In contrast to A. thaliana, auxin promotes rhizoid development by positively regulating PpRSL1 and PpRSL2 activity in P. patens. This indicates that even though the same genes control the development of root hairs and rhizoids, the regulation of this transcriptional network by auxin is different in these two species. This suggests that auxin might have controlled the development of the first land plant soil anchoring systems that evolved 465 million years ago by regulating the expression of RSL genes and that this regulatory network has changed since mosses and angiosperms last shared a common ancestor.
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http://dx.doi.org/10.1242/dev.060582DOI Listing
June 2011